Genmab A/S and AbbVie Inc. have clarified that overall survival was the sole United States primary endpoint in the Phase 3 EPCORE DLBCL-1 trial of epcoritamab monotherapy, and that the study did not meet this endpoint. The July 23, 2026 disclosure does not invalidate the trial’s previously reported progression-free survival benefit, but it materially changes how the study should be interpreted in the United States, where Epkinly remains approved for certain third-line or later diffuse large B-cell lymphoma indications under the accelerated approval pathway.
The clarification is not a new clinical readout. It is a correction to the regulatory framing surrounding a dataset first reported in January 2026 and presented in greater detail at the European Hematology Association Congress in June. EPCORE DLBCL-1 produced evidence that epcoritamab delayed disease progression and generated deeper, more durable responses than investigator-selected chemoimmunotherapy, but it did not demonstrate a statistically significant overall survival improvement.
That distinction matters because the United States Food and Drug Administration specifically identified overall survival as the primary endpoint for the randomized study required to confirm the clinical benefit of Epkinly in relapsed or refractory large B-cell lymphoma. Progression-free survival and response measures were listed as secondary endpoints for that postmarketing requirement. The positive progression-free survival result therefore remains clinically informative, but it does not mean the designated United States confirmatory endpoint was achieved.
Why does the sole US primary endpoint distinction materially change the Phase 3 trial interpretation?
EPCORE DLBCL-1 was designed with different primary endpoint structures across regulatory regions. The current clinical trial registry describes overall survival as the primary endpoint for the United States and China, while overall survival and progression-free survival were dual primary endpoints for the rest of the world. This regional structure means the same clinical results can produce different formal conclusions depending on the regulator evaluating the programme.
For regulators operating under the dual endpoint framework, the statistically significant progression-free survival result can support the conclusion that one of the study’s principal efficacy objectives was achieved. For the United States, however, the formal result is more direct: the sole primary endpoint was overall survival, the hazard ratio was 0.96, the confidence interval crossed 1.00, and the difference was not statistically significant.
The July clarification resolves an important ambiguity created when EPCORE DLBCL-1 was described more broadly as having progression-free survival and overall survival as dual primary endpoints. That description reflected the global trial architecture but did not adequately communicate the United States-specific statistical framework.
This is more than clinical-trial housekeeping. Endpoint hierarchy determines which hypotheses a study was statistically designed to test, how multiplicity is controlled and whether a trial can formally be called successful for a particular regulatory purpose. A meaningful secondary endpoint cannot automatically be promoted to primary endpoint status after the trial has reported.
What did EPCORE DLBCL-1 show despite missing the United States survival endpoint?
The randomized, open-label study enrolled 483 adults with relapsed or refractory large B-cell lymphoma who were ineligible for high-dose chemotherapy and autologous stem cell transplantation or had relapsed after transplantation. Participants were assigned to epcoritamab monotherapy or investigator-selected chemoimmunotherapy consisting of rituximab with gemcitabine and oxaliplatin, or bendamustine with rituximab.
The study population reflected a difficult treatment setting. The median age was 71 years, 73% of patients had received at least two previous lines of systemic treatment, 69% were refractory to their most recent therapy, 15% had undergone a previous stem cell transplant and 11% had received chimeric antigen receptor T-cell therapy.
Epcoritamab produced a progression-free survival hazard ratio of 0.74, representing a 26% relative reduction in the risk of disease progression or death compared with the chemoimmunotherapy arm during the analysed follow-up. The complete response rate was 38% with epcoritamab and 26% with chemoimmunotherapy, while median duration of response was reported at 37 months and six months, respectively. Time to the next lymphoma treatment was also longer with epcoritamab.
These results indicate that patients who responded completely to epcoritamab could experience prolonged disease control. They also provide randomized evidence supporting the biological and clinical activity previously observed in the single-arm EPCORE NHL-1 programme.
Overall survival told a less convincing story. The hazard ratio of 0.96, with a 95% confidence interval of 0.77 to 1.20, showed no statistically significant survival advantage. The estimated 24-month overall survival rate was 38% with epcoritamab and 33% with chemoimmunotherapy, but that numerical difference was not sufficient to establish that epcoritamab prolonged life.
Why can COVID-19 mortality and subsequent therapy complicate survival without rescuing the endpoint?
Investigators reported that interpretation of overall survival was complicated by deaths associated with COVID-19 and by the availability of effective lymphoma treatments used after patients discontinued their assigned therapy. A substantial proportion of enrolment occurred during the Omicron phase of the pandemic, when immunocompromised patients with haematological malignancies faced elevated infection risks.
Overall survival can be influenced by events that occur long after the assigned study treatment has stopped. Patients in the comparator group who progress and subsequently receive bispecific antibodies, cellular therapies or other active agents may live longer even though their original randomized treatment controlled the disease for a shorter period. Conversely, deaths unrelated to lymphoma progression can weaken the connection between treatment activity and the final survival analysis.
These factors help explain why progression-free survival, response durability and overall survival may move in different directions. They do not, however, convert a statistically negative primary analysis into a positive result.
The EHA presentation discussed exploratory analyses intended to assess the potential influence of pandemic-related mortality and subsequent treatment. Such analyses may assist regulators and clinicians in understanding the dataset, but they remain post hoc. They cannot replace the prespecified intent-to-treat analysis on which the United States primary endpoint was judged.
Could the missed survival endpoint place Epkinly’s accelerated approval at risk?
The United States Food and Drug Administration granted Epkinly accelerated approval in May 2023 for adults with relapsed or refractory diffuse large B-cell lymphoma, including disease arising from indolent lymphoma, and high-grade B-cell lymphoma after two or more lines of systemic therapy. That decision was based primarily on response rate and duration of response from the single-arm EPCORE NHL-1 trial.
Accelerated approval allows a medicine to reach patients on the basis of an endpoint considered reasonably likely to predict clinical benefit, provided that the sponsor completes confirmatory research. The FDA can grant traditional approval when benefit is verified, but it also has procedures that can lead to an indication being modified or withdrawn when the required evidence does not confirm sufficient clinical benefit.
For Epkinly, the FDA’s public accelerated approval database identifies EPCORE DLBCL-1 as the required randomized trial and specifies overall survival as its primary endpoint. The database continues to classify the DLBCL indication as an ongoing accelerated approval rather than an approval with verified clinical benefit.
Failure of the specified endpoint does not trigger immediate or automatic market withdrawal. Epkinly remains approved for its existing United States indication unless the FDA and the companies complete a formal regulatory process that changes the label or approval status.
The agency could examine the totality of evidence, including progression-free survival, response durability, safety, treatment exposure, pandemic effects, subsequent therapies and data from other epcoritamab studies. It could request further analyses or additional clinical evidence. It could also determine that the confirmatory requirement has not been fulfilled and consider regulatory action. Genmab and AbbVie have not announced which pathway the FDA may take, and the clarification did not disclose a new regulatory decision.
Does the progression-free survival benefit still have meaningful clinical value?
A negative overall survival endpoint should not erase the progression-free survival and response findings. For patients with relapsed or refractory DLBCL who cannot undergo transplantation, delaying progression and producing durable complete responses can be clinically important, particularly when conventional salvage chemoimmunotherapy has limited durability.
Epcoritamab also offers an off-the-shelf, subcutaneously administered bispecific antibody approach. Unlike autologous cellular therapy, it does not require patient-specific manufacturing. That accessibility can be important for older patients, rapidly progressing disease and treatment centres without extensive cellular therapy infrastructure.
The practical value is balanced by continuing treatment and monitoring requirements. Epcoritamab was administered through repeated 28-day cycles until disease progression or unacceptable toxicity, while the comparator regimens were given for a limited number of cycles. Longer exposure provides more opportunity for both benefit and adverse events to accumulate.
This difference is especially relevant when interpreting safety percentages. Grade 3 or 4 infections were reported in 30% of epcoritamab-treated patients and 12% of patients receiving chemoimmunotherapy. However, exposure-adjusted rates of severe infection were similar because epcoritamab patients generally remained on treatment substantially longer.
Cytokine release syndrome occurred in 53% of patients receiving epcoritamab, with Grade 3 events in 3%. Immune effector cell-associated neurotoxicity syndrome occurred in 4%, including Grade 3 or 4 events in 1%. These toxicities are established risks of CD3-directed bispecific antibodies and require step-up dosing, monitoring and institutional preparedness.
Why are Genmab and AbbVie increasingly relying on combination and fixed-duration studies?
The clarification increases the strategic importance of the wider epcoritamab development programme. A single monotherapy study no longer offers a straightforward route to confirming the United States DLBCL indication through its designated survival endpoint, so evidence from other randomized settings may become more influential in shaping the product’s long-term clinical and commercial position.
Genmab recently reported that the Phase 3 EPCORE DLBCL-4 trial of fixed-duration epcoritamab plus lenalidomide produced a statistically significant progression-free survival improvement over rituximab, gemcitabine and oxaliplatin in previously treated DLBCL. Full results and detailed safety findings have not yet been published, and the trial evaluates a combination rather than the currently approved epcoritamab monotherapy regimen.
EPCORE DLBCL-2 is testing epcoritamab with standard R-CHOP therapy in newly diagnosed DLBCL, while additional programmes are evaluating fixed-duration and chemotherapy-free strategies in different patient groups. Results from these studies could support new indications or treatment regimens if their benefit-risk profiles and statistical endpoints satisfy regulators.
They cannot automatically serve as direct confirmation of the existing third-line monotherapy indication. Different treatment combinations, disease stages and patient populations represent distinct regulatory questions. Their importance lies in showing whether epcoritamab can become a broader lymphoma platform rather than remaining dependent on a single accelerated approval.
What does the clarification mean for Genmab, AbbVie and investor sentiment?
Epkinly is already becoming a meaningful commercial product for Genmab. Global Epkinly and Tepkinly net sales reached $137 million during the first quarter of 2026, up 52% from $90 million a year earlier. Growth was attributed to use in third-line or later DLBCL and follicular lymphoma, together with the newer second-line follicular lymphoma combination indication in the United States.
Genmab recorded $106 million of Epkinly sales in the United States and Japan during the quarter, while sales in territories where the company receives royalties totalled $31 million. The company shares United States and Japanese commercial responsibilities with AbbVie, while AbbVie leads commercialisation in most other markets.
The regulatory uncertainty is proportionally more important for Genmab because Epkinly is one of the company’s principal owned and co-commercialised growth assets. AbbVie has a much larger and more diversified revenue base, making the financial effect of a single lymphoma indication less significant at group level.
Genmab’s Copenhagen-listed shares closed at DKK1,904 on July 23, down 0.37% for the session but approximately 11% above their June 23 close. The stock remained between its reported 52-week low of DKK1,337 and high of DKK2,257. AbbVie shares gained 1.43% on July 23 to close at $256.92, around 1.8% below their 52-week high.
Those closing movements should not be treated as a clean verdict on the clarification, particularly because announcement timing, broader market conditions and company-specific factors can affect daily prices. Investor attention is more likely to centre on the FDA’s response, publication of the complete Phase 3 dataset, upcoming EPCORE DLBCL-2 results and Genmab’s half-year financial report scheduled for August 6.
The critical test is no longer whether epcoritamab demonstrated antitumour activity. EPCORE DLBCL-1 provided randomized evidence of progression-free survival improvement, higher complete response rates and substantially longer response durability. The unresolved question is whether that evidence, despite the missed overall survival endpoint selected by the FDA, will be sufficient to preserve the current accelerated approval pathway or whether Genmab and AbbVie will need a different confirmatory strategy.
